US5804560A - Peptide and peptide analog protease inhibitors - Google Patents
Peptide and peptide analog protease inhibitors Download PDFInfo
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- US5804560A US5804560A US08/369,422 US36942295A US5804560A US 5804560 A US5804560 A US 5804560A US 36942295 A US36942295 A US 36942295A US 5804560 A US5804560 A US 5804560A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to peptidyl compounds useful for a variety of physiological end-use applications. More specifically, di- and tripeptide analogs that are useful in the treatment of neurodegenerative disease states and in the treatment of the degeneration of the neuronal cytoskeleton are provided.
- Di- and tri-peptide compounds and methods of treating certain disorders, particularly cognitive disorders, and methods of inhibiting proteases are provided.
- the methods use compounds having formulae: ##STR2## or the hydrates and isosteres, diastereomeric isomers and mixtures thereof, or pharmaceutically acceptable salts thereof in which:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R A , R e , X, Q and n are selected from among (i), (ii), (iii), (iv), (v), (vi), (vii) or (viii) as follows:
- R 1 , R 3 , R 5 , and R B are each independently selected from a side chain of a naturally occurring ⁇ -amino acid, H, alkyl, preferably lower (C 1-6 ) alkyl, alkenyl, preferably C 2-10 alkenyl, alkynyl, preferably C 2-6 alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, Y-substituted aryl, aralkyl, aralkenyl, aralkynyl, and Z-substituted heteroaryl, heteroaralkyl, heteroaralkenyl, in which Y is selected from halogen, lower alkyl, alkoxy, OH, haloalkyl, preferably CF 3 , NO 2 , nitrile, S-alkyl, phenyl, and --NRR,
- R 2 , R 4 , R 6 , and R 8 are each independently selected from among H and lower alkyl, preferably C 1-4 alkyl;
- R 7 is selected from among C 1-6 alkyl, aryl, alkenyl, 9-fluoroenyl, aralkyl, aralkenyl, aralkynyl the aryl groups are unsubstituted or are substituted with Z;
- Q is selected from among --C(O)--, --O--C(O), --S(O) 2 -- and HN--C(O)--;
- n zero or one
- R A is -(T) m -(D) m -R 1 in which T is O or NH, and D is C 1-4 alkyl or C 2-4 alkene; and m is zero or one;
- X is selected from --(CH 2 ) r C(O)H, --(CH 2 ) r C(O)haloalkyl, --(CH 2 ) r C(o)(CH 2 ) r CHN 2 , --C(CH 2 ) r (O)C(CH 2 ) r (O)OR D , --(CH 2 ) r C(O)(CH 2 ) r C(O)NR D R D , --(CH 2 ) r C.tbd.N. --(CH 2 ) r C(OH)(CH 2 ) r C(O)U.
- R D is selected from among H, alkyl, preferably lower alkyl, more preferably C 1-4 alkyl, phenyl, benzyl, and phenethyl;
- U is --OR D or --NR D R D , and W is --OR D , --SR D , and --NR D R D , or heterocyclic moiety, preferably containing 4-6, more preferably 5 or 6 members in the ring, and preferably one or two heteroatoms, selected from O, S, or N, in the ring, and r is 0-5, preferably 0-3, more preferably 0 or 1, most preferably 0; or
- R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , X and Y are selected as in (i), (iv) or (v);
- V is OH, halogen, lower alkyl, preferably methyl or ethyl or halogen-substituted lower alkyl, preferably methyl or ethyl, and is preferably preferably OH;
- n zero;
- R 6 and R 7 are each independently selected as follows:
- R 6 and R 7 are unsubstituted or substituted with one or more substituents selected from Y or preferably V Which is selected from OH, halogen, lower alkly preferably methly or ethethyl, or hallogen substituted lower alkkly, preferably methyl or ethyl, and is more preferably OH,
- heterocyclic moiety preferably a 5-6 atomed heterocyclic moiety, more preferably selected from among morpholino, thiomorpholino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4-hydroxy pyrrolidinyl; or
- R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R A , X and R B are selected as in (i);
- V is as defined in (ii);
- n one;
- R 6 and R 7 are each independently selected as follows:
- each is unsubstituted or substituted with Y. preferably with V, and
- R 6 and R 7 are selected with the proviso that when two or more heteroatoms are present there is a carbon atom between the heteroatoms;
- the moiety when the moiety is a heterocycle, it is preferably succinimide, phthalimide or maleimide; or
- R 3 , R 4 , R 5 , R 6 , R 7 , R A , R B , Q, X and n are as defined in any of (i)-(iii) or (v)-(viii),
- V is as defined in (ii);
- R 8 is H
- R 1 and R 2 are each independently selected as follows:
- R 1 and R 2 are unsubstituted or substituted with Y, preferably with V, and
- heterocyclic moiety preferably a 4-6 membered heterocyclic moiety, that is preferably morpholino, thiomorpholino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4-hydroxy pyrrolidinyl; or
- R 1 R 2 f R 5 , R 6 , R 7 , R 8 , R A , R B , X, Q and n are as defined in any of (i)-(iv) or (vi)-(viii);
- V is as defined in (ii);
- R 3 and R 4 are each independently selected as follows:
- (b) is unsubstituted or substituted with Y, preferably with V, and
- heterocyclic moiety preferably a 4-6 membered heterocyclic moiety, that is preferably morpholino, thiomorpho-lino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4-hydroxy pyrrolidinyl; or
- R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , Q, X and n are as defined in any of (i), (iv) or (v);
- V is as defined in (ii);
- R 5 and R 6 are each independently selected as follows:
- R 5 and R 6 are unsubstituted or substituted with Y, preferably with V, and
- heterocyclic moiety preferably a 4-6 membered heterocyclic moiety, that is preferably morpholino, thiomorpholino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4hydroxy pyrrolidinyl; or
- R., R 2 , R 3 , R 4 , R 6 , R 8 and X are selected as in (i) (iv) or (v);
- V is as defined in (ii);
- n zero;
- R 5 and R 7 are each independently selected as follows:
- R 5 and R 7 are unsubstituted or substituted with Y, preferably with V, and
- heterocyclic moiety preferably a 4-6 membered heterocyclic moiety, that is preferably morpholino, thiomorpho-lino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4-hydroxy pyrrolidinyl; or
- R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , X and Y are selected as in (i), (iv) or (v);
- V is as defined in (ii);
- R 6 and R 7 which are defined as in (ii), together with the atoms to which each is attached form a bicyclic heterocycle or cyclic moiety, preferably, when n is zero, a reduced isoquinoline, and is preferably 1,2,3,4, tetrahydroisoquinoline;
- the carbon chains which may be straight or branched, contain from 1 to about 12 carbons preferably 1 to 6, and most preferably 4-6 carbons, and the cyclic moieties preferably contain one ring or two fused rings with from 3 to 16 atoms, preferably 4 to 12, with 4 to 6 in each ring, in the ring structures.
- the ⁇ -amino acids of the compounds of formulae I and II are preferably in their L-configuration.
- R 1 is S
- R 3 is S
- R 5 is R/S.
- a compound of these formulae may be in free form, e.g., an amphoteric form, or a salt form, e.g., an acid addition or an anionic salt.
- a compound may be converted to its salt or base form in an art-known manner, one from another.
- Preferred salts are trifluoracetate, hydrochloride, sodium, potassium or ammonium salts, although the scope of the salts embraced is not limited thereto, the scope being extended to include all of those salts known to be used in the art of chemistry.
- Compounds are also provided herein. These compounds may be used in the methods.
- the compounds have formulae I or II as defined above, but with the proviso that, when the compounds have formula (I): (1) at least one of the amino acid residues in the resulting tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) when X is an aldehyde, the non-naturally occurring amino acid (or side chain thereof) is other than norleucine or norvaline, and when the compounds have formula (II) and X is an aldehyde, R 1 cannot be the side chain of norleucine or norvaline.
- the compounds of formula (II) are also selected such that: (1) at least one of the amino acid residues in the resulting di-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 and R 3 is not a side chain of a naturally-occurring amino acid; and (2) when X is an aldehyde, the non-naturally occurring amino acid (or side chain thereof) is other than norleucine or norvaline.
- the compounds have formulae I or II, particularly formula I as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting di or tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) when R 1 is the side chain from a non-naturally occurring amino acid, it is not the side chain of norleucine or norvaline.
- the compounds have formulae I or II, particularly when the compounds have formula 1, as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting di or tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) none of R 1 , R 3 and R 5 is the side chain of norleucine or norvaline.
- the compounds provided herein are preferred for use in the methods, particularly the methods of treatment of cognitive disorders.
- compositions containing a compound of formulae (I) and (II) are provided.
- pharmaceutical compositions formulated for single dosage administration are provided.
- Methods of treatment of diseases, particularly cognitive disorders are provided and are effected by administering an effective amount of the pharmaceutical compositions.
- a neurodegenerative disease selected from among Alzheimer's disease, cognition deficits, Down's Syndrome, Parkinson's disease, cerebral hemorrhage with amyloidosis, dementia pugilistica, head trauma and any disorder characterized by an accumlation of plaques in the brain, by administering to the patient a therapeutically effective amount of a compound of formulae (I) and (II) or compounds of formulae (I) and (II) in which R 1 , R 3 , R 5 and R B can all be side chains of naturally-occurring amino acids are provided.
- Methods of treating a patient suffering from a disease state characterized by the degeneration of the cytoskeleton arising from a thrombolytic or hemorrhagic stroke by administering a therapeutically effective amount of a compound of formulae (I) and (II) are provided.
- Assays for detecting compounds that modulate the processing of amyloid precursor protein (APP) and other related proteins are also provided.
- assays that detect a relative decrease in the amount of amyloidogenic A ⁇ peptide produced by cultured cells that express APP such as cultured human glioblastoma cell lines that have been transfected with DNA encoding either a wild-type 695 amino acid isoform of APP or a mutein of APP are provided.
- a positive in vitro assay occurs when: (1) there is a decrease in the ⁇ 4-kDa amyloid ⁇ -protein (A ⁇ ) in the medium relative to control cultures; and/or (2) the relative amount of soluble APP (referred to as sAPP, also s ⁇ PP and total soluble APP) in the medium increases; and/or (3) there is a decrease in the amount of C-terminal fragments of APP larger than 9 kDa in the cell lysate as a result of differential processing; and/or (4) there is an increase in the amount of ⁇ -sAPP in the medium relative to control cultures.
- a ⁇ amyloid ⁇ -protein
- Methods of detecting markers indicative of neurodegenerative disorders characterized by deposition of cerebral amyloid by detecting a decrease in the ratio of ⁇ -sAPP to total sAPP or a decrease in the amount of ⁇ -sAPP in a sample of CSF compared to such ratio or amount in control CSF from individuals who do not have this disorder or compared to predetermined standard ratios and amounts, are also provided herein.
- Methods of identifying compounds that are effective for treating patients with neurodegenerative disorders characterized by deposition of cerebral amyloid by administering the compound to a subject and detecting an increase in the ratio of ⁇ -sAPP to total sAPP or an increase in the amount of ⁇ -sAPP in a sample of CSF from the subject compared to such ratio or amount in a sample of CSF prior to administering the compound are also provided herein.
- alkyl includes the straight, branched-chain and cyclic manifestations thereof, the number of carbon atoms is generally specified. Where not specified the alkyl groups preferably contain from about 1 up to about 10 or 12, more preferably 1 to 6 or 7, and most preferably 4 to 6 carbons.
- moieties are methyl, ethyl, propyl, cyclopropyl, isopropyl, n-butyl, t-butyl, sec-butyl, cyclobutyl, pentyl, cyclopentyl, n-hexyl, n-nonal, n-decyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, and the like.
- Lower alkyl refers to alkyl groups containing six or fewer carbon atoms.
- heteroatoms are selected from O, N or S.
- aryl within the definitions of X, R B , R 1 , R 3 , R 5 , and R 7 includes carbocyclic and heterocyclic moieties.
- Preferred aralkyl and aryl moieties are phenyl, benzyl, phenethyl, 1- and 2-naphthalmethyl, 1- and 2-naphthyl, 2-,3-, 4- pyridyl, 2- and 3-furyl, 1- and 2-indenyl, 1- and 2- thiophenyl, imidazolyl, indolyl, 2- and 3-thienyl, indole-3-ethyl and the residue of 1,2,3,4, tetrahydroisoquinoline.
- carbocycles are such fused moieties as pentalenyl, indenyl, naphthaleneyl, naphthylmethyl, azulenyl, heptalenyl, acenaphthylenyl, 9-fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, triphenylenyl, pyrenyl, chryrsenyl, and naphthacenyl.
- alkynyl is propynyl.
- alkenyl moieties are 2-methyl-2-propenyl, 2-methyl-1-propenyl, propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-di-fluoroethenyl, as well as those straight and branched chained moieties having up to two double bonds.
- Cyclic carbon moieties preferably contain one or two fused rings typically from 3 up to about 16, preferably 4 up to about 12 carbons.
- Haloalkyl embraces such moieties as CF 3 , --CF 2 H, --CFH 2 , CH 2 Cl and CH 2 Br and other halo substituted lower alkyls.
- exemplary of aryloxyalkenyl and aryloxyalkynyl moieties of R A are phenoxymethyl, CF 3 -substituted phenoxymethyl,benzyloxymethyl,phenoxybutyr-2-ene, 1 -phenyl- 1 -propene, CF 3 -phenoxybutyr-2-ene, CF 3 -benzyloxymethyl, these moieties are preferred when R A is other than R 1 .
- each ⁇ -amino acid has a characteristic "R-group," the R-group being the residue -or side chain- attached to the ⁇ -carbon atom of the amino acid.
- R-group being the residue -or side chain- attached to the ⁇ -carbon atom of the amino acid.
- the residue of glycine is H, for alanine it is methyl, for valine it is isopropyl.
- the specific residues of the naturally occurring ⁇ -amino acids are well known to those of skill in this art see, e.g, A. L. Lehninger, Biochemistry: The Molecular Basis of Cell Structure and Function, 1970 (or any edition thereafter), Worth Publishers, NY, see, particularly Chapter 4).
- residues of naturally occurring ⁇ -amino acids are the residues of those 20 ⁇ -amino acids found in nature which are incorporated into protein by the specific recognition of the charged tRNA molecule with its cognate mRNA codon in humans.
- the moieties in the peptide analogs provided herein are designated according to the system of nomenclature in which the binding region of a proteinase is considered as a series of subsites, S, along the surface of the enzyme see, Schecter and Berger (Biochem. Biophys. Res. Comm., 27, 157-162 (1967)!. Each subsite binds an individual peptide residue, P.
- This system of nomenclature originally designed for papain, has been adapted to other proteases.
- the moiety bearing the R 1 side chain (or residue) is designated as the P 1 moiety
- the moiety bearing the R 3 side chain (or residue) is designated as the P 2 moiety
- that which bears the R 5 moiety is designated as the P 3 moiety.
- the N-terminal capping moieties represented by the R 7 --(Q) n-- and (R B )--CH(R A )--(Q)n-- include those moieties that protect molecules from degradation by aminopeptidases and include, but are not limited to, such generic groupings as arylcarbonyl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, aralkylsulfonyl, alkylsulfonyl, arylsulfonyl, and other equivalently functioning groups known in the art.
- alkyl means a linear, cyclic, or branched-chain aliphatic moiety of 1 to 20 carbon atoms
- aryl means an aromatic moiety, e.g., phenyl, of 6 to 18 carbon atoms, unsubstituted or substituted with one or more alkyl, substituted alkyl, nitro, alkoxy, or halo groups
- substituted alkyl means an alkyl group having a substituent containing a heteroatom or heteroatoms such as N, O, or S
- halo means Cl or Br
- alkaryl means an aryl moiety of 6 to 19 carbon atoms having an aliphatic substituent, and, optionally, other substituents such as one or more alkyl, substituted alkyl, alkoxy or amino groups.
- N-terminal blocking groups include, but are not limited to, formyl, t-butyloxycarbonyl, isopropyloxycarbonyl, allyloxycar-bonyl, acetyl, trifluoracetyl, methyl, ethyl, benzyl, benzoyl, acetoacetyl, chloroacetyl, succinyl, phthaloxy, phenoxycarbonyl, methoxysuccinyl, p-methoxybenzenesulfonyl, p-toluenesulfonyl, isovaleroyl, methanesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, adipyl, suberyl, phthal-amido-, morpholino-, azelayl, dansyl, tosyl, 2,4-dinitrophenyl, fluorenyl-methoxycarbonyl, me
- an effective amount of a compound for treating a disorder is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
- treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
- amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
- substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography TLC!, gel electrophoresis and high performance liquid chromatography HPLC!, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
- Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art.
- a substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.
- biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmaceutical activity of such compounds, compositions and mixtures.
- pharmaceutical activity refers to the activity of the compounds herein to treat a disorder.
- the IC 50 refers to an amount, concentration or dosage of a particular compound that achieves a 50% inhibition of a maximal response.
- EC 50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
- a prodrug is a compound that, upon In vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound.
- the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
- the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
- amyloid precursor protein is the progenitor of deposited amyloidogenic A ⁇ peptides (A ⁇ ) found in the senile plaques in patients with diseases, such as Alzheimer's disease (AD), that are characterized by such deposition.
- ⁇ -sAPP is an alternative cleavage product of APP; its formation precludes formation of A ⁇ .
- Cha is cyclohexylalanine.
- the compounds of formula (II) are also selected such that: (1) at least one of the amino acid residues in the resulting di-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 and R 3 is not a side chain of a naturally-occurring amino acid; and (2) when X is an aldehyde, the non-naturally occurring amino acid (or side chain therof) is other than norleucine or norvaline.
- the compounds have formulae (I) or (II), particularly formulae (I) as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting di or tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) when R 1 is the side chain from a non-naturally occurring amino acid, it is not the side chain of norleucine or norvaline.
- the compounds have formulae (I) or (II), particularly formulae (I), as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting di or tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) none of R 1 , R 3 and R 5 is the side chain of norleucine or norvaline.
- R 1 , R2, R3, R4, R5, R6, R7, R8, R A , R B , X, Q and n are selected from among (i), (ii), (iii), (iv), (v), (vi), (vii) or (viii) as described above.
- R 1 is preferably a straight or branched chain carbon chain containing 2 to 6 carbons and one unsaturated, preferably a double bond, or is a cyclic moiety containing from 5 to 6 members, and is more preferably 2-methyl propene, 2-butene, cyclohexyl, lower alkyl-substituted cyclohexyl or cyclohexylmethyl;
- R 2 , R 4 , and R 8 are each independently selected from among H or C 1-4 alkyl, and more preferably methyl or ethyl;
- R 3 is C 1-4 alkyl, phenyl, Benzyl, naphthyl, hydroxyphenyl, 1-aminobutyl, acetamide, and more preferably iso-butyl Benzyl or phenyl;
- R 5 is C 1-4 alkyl, and more preferably iso-butyl
- R 6 is H or C 1-4 alkyl, and more preferably H or methyl;
- R 7 --(Q) n is acyl, benzyloxycarbonyl (Cbz), 9-fluorenylmethylcarbonate (Fmoc), Ac, Boc, tosyl, with Cbz, Ac and Fmoc being more preferred, and Cbz and Ac most preferred;
- Q is --C(O)--, --S(O) 2 --and --O--C(O), with --C(O)--and --O--C(O) being more preferred, and --O--C(O) most preferred;
- R B is C 1-4 alkyl or C 2-4 alkenyl, and more preferbly iso-butyl;
- R A --(T) --(D) --R, in which T is oxygen, or nitrogen, with oxygen being more preferred, and D is C 1-4 alkyl or C 2-4 alkenyl, with a mono-unsaturated C 3-4 alkenyl being more preferred; and
- X is aldehyde, ⁇ -ketoester ⁇ -ketoamide, trifluoromethylketone, diazomethylketone, or nitrile, with an aldehyde, ⁇ -ketoester or ⁇ -ketoamide being more preferred.
- R 1 , R 3 , and R 5 are a side-chain from other than a residue of a naturally occurring ⁇ -amino acid
- such moiety is a straight or branched carbon chain, preferably containing at least one unsaturated bond, preferably a double bond, and 2 to 10, preferably 4 to 7, more preferably 4-6 carbon atoms in the chain, such as, but not limited to, 2-methyl propene and 2-butene, or is a cylic moiety, preferably containing 4-6 members, more preferably is cyclohexylmethyl.
- the resulting residues including such moieties include, but are not limited to, 2-amino-4-methyl-4-pentenoic acid, 2-amino-4-hexenoic acid, cyclohexylalanine and cyclohexyl-glycine, with (2S)-2-amino-4-methyl-4-pentenoic acid and (2S)-2-amino-4-hexenoic acid being preferred.
- the side chains from norvaline and leucine are also preferred.
- preferred compounds are those in which at least one of R 1 , R 3 , and R 5 is 2-methyl-propene, 2-butene, cyclohexyl or cyclohexylmethyl. More preferred are those in which R 1 , R 3 , and R5 are 2-methyl-propene, 2-butene, cyclohexyl or cyclohexylmethyl, and X is C(O)H, C(O)--C(O)OR D , C(O)--C(O)--NR D R D , C(O)CHN 2 , C(O)CF 3 , or C.tbd.N.
- Preferred heterocyclic ring moieties containing R 1 and R 2 and the atoms to which they are attached, when R 8 is H, are morpholino, thiomorpholino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4-hydroxy pyrrolidinyl.
- Preferred heterocyclic ring moieties containing R 6 and R 7 and the atoms to which they are attached when (Q) n is a carbonyl group are selected from among succinimide, phthalimide or maleimide, with phthalimide being more preferred.
- Preferred heterocyclic ring moieties containing R 6 and R 7 and the atoms to which they are attached when n in (Q) n is zero are morpholino, thiomorpholino, pyrrolidinyl, V-substituted pyrrolidinyl, particularly 4-hydroxy pyrrolidinyl, or 1,2,3,4-tetrahydroisoquinoline.
- V form heterocyclic moieties are morpholino, thiomorpholino, pyrrolidinyl, or V-substituted pyrrolidinyl, particularly 4-hydroxy pyrrolidinyl.
- ⁇ -ketoesters and ⁇ -ketoamides of any of the above listed compounds.
- R 2 and/or R 4 and/or R 6 are methyl (i.e., the N-methyl derivatives of the compounds).
- N-methyl-N-methoxyamide derivatives (sometimes referred to as a Weinreb amide) are coupled to a N-protected dipeptide (4) to produce the analogous N-methyl-N-methoxyamide intermediates (5) which are reduced to the desired aldehydes using standard reduction conditions, e.g., by the use of lithium aluminum hydride (LiAlH 4 ) in tetrahydrofuran (THF) at about 0° C. in an inert atmosphere (Ar or N 2 ) under anhydrous conditions. After the reaction is complete, about 30 min, the reaction is quenched by the addition of, for example, 10% potassium hydrogen sulfate and then water.
- LiAlH 4 lithium aluminum hydride
- THF tetrahydrofuran
- the esters (1) are subjected to mild hydrolysis using LiOH and hydrogen peroxide in a methanol-water solvent according to known conditions.
- the resulting amino acids are coupled with propane sulfide to produce the thioesters (2) which are reduced to their corresponding aldehyde by using Pd on carbon with triethylsilane under anhydrous conditions at room temperature under an inert atmosphere.
- Reaction Scheme D illustrates the preparation of precursor reactants which are amendable to substitutions on the ⁇ -carbon atom; these substituents not necessarily being residues of naturally occurring ⁇ -amino acids.
- N-(diphenylmethylene)glycine ethyl ester (1) is treated with lithium bis(trimethylsilyl)amide wherein the reaction is effected in THF under an inert atmosphere at temperatures of about -78° C. and the in situ generated base is reacted with the appropriate alkyl halide to effect a nucleophilic displacement.
- the so-alkylated intermediates (2) and (4) are subjected to hydrolysis to produce the amines (3) and (5) which are available for appropriate use in the construction of the desired dipeptides and tripeptides wherein R 1 , R 3 or R 5 are side chains other than that of a naturally occurring ⁇ -amino acid. Similar such process may be useful in preparing compounds in which R 2 , R 4 or R 6 is an alkylated product.
- Reaction Scheme E illustrates the preparation of the P1 moiety wherein X is nitrile.
- the synthesis is initiated by reacting an N-protected amino acid with iso-butyl chloroformate in the presence of 4-methylmorpholine at -78° C. under an inert atmosphere and the resulting mixed anhydride derivatives are treated with ammonia gas at -78° C. to form the corresponding amides (2).
- the amide is converted to its nitrile by dehydration with tosyl chloride in pyridine followed by the removal of the Boc protecting group by hydrolysis with 4N HCl in dioxane.
- the P1 moieties are coupled with the appropriate P 2 P 3 moiety (A-5 4), or with the appropriate P 2 moiety (J-5) to produce the nitriles of E-5 or in the case of coupling with the P 2 moiety of J-5, the corresponding nitrile analogues to the aldehydes (J-7)!.
- Reaction Scheme F illustrates the preparation of compounds of a P1 moiety wherein X is a C(O)W, defined as above, C 1-6 alkyl or aralkyl.
- the N-methyl-N-methoxyamide derivative (1) is treated with a lithiothiazole nucleophile generated in situ to produce a ketothiazole which is deprotected by hydrolysis with 4N HCl in dioxane to obtain compounds (2) which are then coupled to the appropriate P 2 P 3 moieties to obtain the derivatives of compound (3) or with the appropriate P 2 moieties (i.e., (R A )CH(R B )--C(O)N(R 4 )--CH 2 (R3)C(O)OH) to obtain the desired dipeptides.
- the appropriate P 2 moieties i.e., (R A )CH(R B )--C(O)N(R 4 )--CH 2 (R3)C(O)OH
- lithio derivative of thiazole may be replaced with litho derivatives of other aryl, aralkyl and alkyl moieties and by following substantially the same procedures, the corresponding di- and tri- peptides may be obtained.
- Reaction Scheme G illustrates the preparation of compounds of formulae I and II wherein the X moiety is a haloketone.
- the reaction is initiated by reacting an R 1 -substituted nitromethane with a trifluoromethyl acetal (2) in DMF in the presence of potassium carbonate at about 60° C. to yield a 1,1,1-trifluoro-2-hydroxy-3-nitro derivative (3) which are reduced with H 2 in the presence of Raney Nickel to yield the corresponding amines (4).
- the alcohols of (6) may be produced which would then be subjected to Dess-Martin oxidation to produce the desired CF 3 analogues (7).
- mono- and di-fluoromethyl analogues of formula (2) and by following substantially the same procedures, there are produced the corresponding --CH 2 F and --CHF 2 ketone analogues.
- Reaction Scheme H illustrates the preparation of compounds of formulae I and II wherein the X represents an ⁇ -ketoester or ⁇ -ketoamide (C(O)C(O)OR D or C(O)C(O)NR D R D , respectively).
- the peptides are subjected to a modified Dakin West reaction to generate an enol ester which is subjected to a basic hydrolysis to obtain the ⁇ -keto esters (2).
- the ketone is protected by a ketal formation by reaction with HSCH 2 CH 2 SH in the presence of a BF 3 etherate.
- Treatment with ethanol at 0° C. in the presence of the appropriate amines forms the amide moiety and deprotects the ketal to form the ⁇ -keto amide (4).
- hydrolysis of intermediate (2) produces the ⁇ -keto acid (5).
- Reaction Scheme 1 illustrates the preparation of compounds of formulae I and II wherein the X moiety is a diazomethane which may be converted to a halomethyl ketone.
- the amine protected peptides are subjected to reaction with iso-butyl chloroformate in the presence of 4-methylmorpholine in CH 2 Cl 2 at -78° C.
- the mixed anhydride derivatives are reacted with diazomethane according to standard procedures well known in the art.
- the diazoketones of formulae 11 may be treated with the appropriate acid (e.g., HF, HCl, HBr), in pyridine to afford the desired ketohalomethyl derivatives.
- Reaction Scheme J illustrates the preparation of compounds of formulae I and II wherein the amino terminus of the peptide is modified to produce compounds embraced within the scope of the R A (R B )--CH--(Q) n --! of formulae II as well as compounds which fall within the scope of R 7 --(Q) n -- of fomulae I wherein (Q) n is C(O).
- the scheme is initiated by the conversion of the acid (1) to its acid chloride.
- Treatment of the acid chloride with the appropriate chiral auxiliary e.g., 4S,5R--(-)-4-methyl-5-phenyl-oxazolidinone
- the hydrolyzed amino acid is subjected to another coupling reaction with an amino acid (in its ester form), and the ester of the resulting dipeptide is reduced with lithium borohydride to its corresponding alcohol (6).
- the alcohol is converted to its aldehyde using the Swern oxidation procedure.
- Reaction Scheme K illustrates the formation of a dipeptide wherein R B may represent an aryloxy, aralkoxy or an alkoxy in an enantiomeric pure isomer.
- the reaction is initiated by a two step process wherein (a) compound (1) is hydrodeaminated by treatment with NaNO 2 in HCl and (b) an esterification of the acid with an alkyl halide in the presence of DMF and cesium carbonate to produce compounds (2).
- Reaction Scheme L illustrates the preparation of compounds of formulae I and II wherein the X is defined by the moiety C(O)CH 2 Y.
- the N-protected diazoketone derivatives of compound (1) are subjected to an addition reaction with an hydrohalic acid, preferably HCl, in pyridine to produce halomethyl derivatives (2), which are subjected to a nucleophilic displacement reaction using an activated anion of the desired Y moiety, (e.g., - Y), to afford compounds (3).
- Standard hydrolysis reactions remove the N-protecting group followed by the usual coupling procedures with the desired P 2 P 3 moieties (e.g., compounds A-4) to produce the desired compounds (5).
- Reaction Scheme M illustrates the preparation of compounds of formulae I and II wherein the X is defined by the moieties (a) --CH(OH)--C(O)--NR D R D and (b) --CH(OH)--C(O)OR D .
- the process conveniently starts with the obtention of the aldehyde (2) by reducing the N-methyl-N-methoxy amide derivative (1), followed by preparation of the cyanohydrin (3) which is hydrolyzed to its free acid (4) using standard and well known reaction techniques.
- Coupling of the desired dipeptides (i.e., the P 2 P 3 moiety) to the acid (4) is effected by the use of an activated iso-butyl chloroformate in the presence of 4-methylmorpholine at -78° C. in an inert atmosphere under anhydrous conditions to afford the acid (5).
- the acids (5) may be esterified to its corresponding ester or may be coupled with an amine (NR D R D ) to produce the desired amides (6).
- analogous dipeptides may be prepared.
- compounds (2) may be transformed to their N-protected (preferably a Boc group) alkyl ester by reaction with ethylacetate in the presence of LDA to produce compounds (8) which are hydrolyzed with 4 N HCl in dioxane to remove the protecting group to produce the corresponding ⁇ -hydroxy ethyl esters (9). These esters are then coupled with compounds (A-4) and the resulting compounds are hydrolyzed to their ⁇ -hydroxy acids or they may be coupled to form their ⁇ -hydroxyamides of compounds (11).
- N-protected preferably a Boc group
- Reaction Scheme N illustrates the process by which compounds of formulae I and II wherein the R 2 , R 4 , or R 6 represent an R D moiety other than H.
- the procedure utilizes standard N-protection, N-alkylation -esterfication and de-protection procedures such as those exemplified in the depicted schemes.
- the reaction scheme depicts N-alkylation at the projected P 1 moiety, any of the P 2 and P 3 moieties may be similarly N-alkylated by appropriate selection of the starting materials followed by the coupling procedures required to construct the desired peptides of formulae I and II.
- tri- and dipeptide analogs of Formulae I and II may be effected using procedures and techniques well known in the art and described herein. Many of the necessary starting materials and the reactants utilized are known and may also be commercially available. In those instances in which they are not generally available, they may readily be generated by analogous use of known chemical processes and techniques readily available in the scientific and patent literature or as described herein.
- the Swern oxidation is effected by reacting 2 to 10 equivalents of dimethyl sulfoxide (DMSO) with about 1 to 6 equivalents of trifluoroacetic anhydride (CF 3 CO) 2 )! or oxalyl chloride -(COCl) 2 !.
- DMSO dimethyl sulfoxide
- CF 3 CO trifluoroacetic anhydride
- oxalyl chloride -(COCl) 2 ! oxalyl chloride -(COCl) 2 !.
- the reactants are dissolved in an inert solvent, e.g., methylene chloride (CH 2 Cl 2 )
- the reactor is under an inert atmosphere under anhydrous conditions at temperatures of about -80° C. to -50° C. to form an in situ sulfonium adduct to which is added about 1 equivalent of the alcohols (e.g., B-4).
- the alcohols are dissolved in an inert solvent, e.g., CH 2 Cl 2 or minimum amounts of DMSO, and the reaction mixture is allowed to warm to about -50° C. (for about 10-20 minutes) and then the reaction is completed by adding 3 to 10 equivalents of a tertiary amine, e.g., triethylamine, N-methyl morpholine, etc. Following oxidation, the desired intermediates are isolated and are ready for the next step in the reaction sequence.
- an inert solvent e.g., CH 2 Cl 2 or minimum amounts of DMSO
- a modified Jones oxidation procedure may conveniently be effected by reacting the alcohols with pyridinium dichromate by contacting the reactants in a water-trapping sieve powder, (e.g., a grounded 3 Angstrom molecular sieve) in the presence of glacial acetic acid at about 5° C. to 50° C., preferably at room temperature.
- a water-trapping sieve powder e.g., a grounded 3 Angstrom molecular sieve
- a chromic anhydride-pyridine complex i.e., a Sarett reagent prepared in situ (see, e , Fieser and Fieser “Reagents for Organic Synthesis” Vol. 1, pp. 145 and Sarett, et al., J.A.C.S. 25, 422 (1953))! that is prepared in situ in an inert solvent (e.g., CH 2 Cl 2 ) in an inert atmosphere under anhydrous conditions at about 0° C. to 50° C. to which complex is added 1 equivalent of the alcohols allowing the reactants to interact for about 1 to 15 hours, followed by the isolation of the desired product.
- an inert solvent e.g., CH 2 Cl 2
- Another alternative process for the converting of alcohols to the desired ketones is an oxidation reaction that employs periodane i.e., 1,1,1-triacetoxy-1,1-dihydro, 1 ,2-benzoxidol 3-(1-H)-one (see Dess Martin, J. Org. Chem. 48, 4155, (1983))!.
- This oxidation is effected by contacting 1 equivalent of the alcohols with 1 to 5 equivalents of periodane (preferably 1.5 equivalents) in suspension in an inert solvent (e.g., CH 2 Cl 2 ) under an inert atmosphere (preferably nitrogen) under anhydrous conditions at about 0° C. to 50° C. (preferably room temperature), and allowing the reactants to interact for about 1 to 48 hours.
- an inert solvent e.g., CH 2 Cl 2
- an inert atmosphere preferably nitrogen
- a solid phase sequential coupling procedure can be performed using established methods such as use of an automated peptide synthesizer.
- an amino protected amino acid is bound to a resin support at its carboxyl terminus, the protected amine is deprotected where the peptide linkage is desired, the amino group neutralized with a base and the next amino protected amino acid in the desired sequence is coupled in a peptide linkage.
- the deprotection, neutralization and coupling steps are repeated until the desired peptide is synthesized.
- the compounds provided herein are thus synthesized from their carboxyl terminal end to their amino terminal end.
- the amino protected amino acid can be a conventional amino acid, a derivative or isomer thereof, or a spacer group.
- the resin support employed can be any suitable resin conventionally employed in the art for the solid phase preparation of polypeptides.
- the preferred resin is polystyrene which has been cross-linked with from about 0.5 to about 3% divinyl benzene, which has been either benzhydrylamidated, chloromethylated or hydroxymethylated to provide sites for amide or ester formation with the initially introduced amino protected amino acid.
- the ⁇ -amino protecting group employed with each amino acid introduced into the polypeptide sequence may be any such protecting group known in the art.
- amino protecting groups contemplated are: (1) acyl type protecting groups such as formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl (tosyl), benzenesulfonyl, nitrophenylsulfonyl, tritylsulfonyl, o-nitrophenoxyacetyl, and ⁇ -chlorobutryl; (2) aromatic urethane type protecting groups such as benzyloxycarbonyl and substituted benzyloxycarbonyls such as r-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyl-oxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl
- ⁇ -amino protecting group is t-butyloxycarbonyl (Boc); its use as an ⁇ -amino protecting group for amino acids is well known to those of skill in the art (see, eq-, by Bodansky et al. in "The Practice of Peptide Synthesis," Springer-Verlag, Berlin (1984), p.20!.
- the ⁇ -amino protecting group may be removed using any suitable procedure such as by using trifluoroacetic acid, trifluoroacetic acid in CH 2 Cl 2 , or HCl in dioxane.
- the deprotection is carried out at a temperature of between 0° C. and room temperature.
- Other standard cleaving reagents may be used for removal of specific amino protecting groups under conditions well known and appreciated in the art.
- the next desired amino-protected amino acid is coupled through a peptide linkage. This deprotection, neutralization and coupling procedure is repeated until a peptide of the desired sequence is obtained.
- multiple amino acid groups may be coupled by the solution method prior to coupling with the resin supported amino acid sequence.
- Other coupling agents are (1) other carbodiimides (e.g., N-ethyl-N'-(y-dimethylaminopropylcarbodiimide); (2) ketenimines; (3) isoxazolium salts (e.g., N-ethyl-5-phenylisoxazolium-3-sulfonate); (4) monocyclic nitrogen-containing heterocyclic amides of aromatic character containing one through four nitrogens in the ring such as imidazolides, pyrazolides, and 1,2,4-triazolides (specific heterocyclic amides that are useful include N,N-carbonyidiimidazole and N,N-carbonyl-di-1,2,4-triazole); (5) alkoxylated acetylene (e.g., ethoxyacetylene); (6) reagents which form a mixed anhydride with the carboxyl moiety of the amino acid (e.g., ethyl chloro
- the preferred coupling method for Gin, Asn and Arg is to react the protected amino acid, or derivatives or isomers thereof, with N,N-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole (1:1) in N,N-dimethylformamide (DMF) in the presence of the resin or resin-bound amino acid or peptide.
- the preferred coupling method for other amino acids involves reacting the protected amino acid, or derivative or isomer thereof, with N,N-dicyclohexylcarbodiimide in CH 2 Cl 2 to form the symmetrical anhydride.
- the symmetrical anhydride is then introduced into the solid phase reactor containing the resin or resin-bound amino acid or peptide, and the coupling is carried out in a medium of DMF, or CH 2 Cl 2 , or DMF: CH 2 Cl 2 (1:1). A medium of DMF is preferred.
- the success of the coupling reaction at each stage of the synthesis is monitored by a ninhydrin test as described by Kaiser et al. Analyt. Biochem. 34, 595 (1970)!. In cases where incomplete coupling occurs, the coupling procedure is repeated. If the coupling is still incomplete, the deprotected amine is capped with a suitable capping reagent to prevent its continued synthesis. Suitable capping reagents and the use thereof are well known and appreciated in the art.
- capping reagents examples include acetic anhydride and acetylimidazole as described by Stewart et al. "Solid Phase Peptide Synthesis,” 2nd Ed., Pierce Chemical Co., Rockford, Ill. (1984), Chapter 2, p.73!.
- the peptide is cleaved from the resin. This can be effected by procedures which are well known and appreciated in the art, such as by hydrolysis of the ester or amide linkage to the resin. It is preferred to cleave the peptide from the benzhydrylamine resin with a solution of dimethyl sulfide, p-cresol, thiocresol, or anisole in anhydrous hydrogen fluoride.
- the cleavage reaction is preferably carried out at temperatures between about 0° C. and about room temperature, and is allowed to continue preferably from between about 5 minutes to about 5 hours.
- p-toluenesulfonyl (tosyl) moieties can be used to protect the amino side chains of amino acids such as Lys and Arg; p-methylbenzyl, acetamidomethyl, benzyl (Bn), or t-butylsulfonyl moieties can be used to protect the sulfide-containing side chains of amino acids such as cysteine, homocysteine, penicillamine and the like or derivatives thereof; benzyl or cyclohexyl ester moieties can be used to protect carboxylic acid side chains of amino acids such as Asp, Glu; a benzyl ether can be used to protect the hydroxyl-containing side chains of amino acids such as Ser and Thr; and a 2-bromocarbobenzoxy (2Br-Cbz) moiety can be used to protect the hydroxyl-containing
- side chain protecting groups are added and removed according to standard practices and procedures well known in the art. It is preferred to deprotect these side chain protecting groups with a solution of anisole in anhydrous hydrogen fluoride (1:10). Typically, deprotection of side chain protecting groups is performed after the peptide chain synthesis is complete but these groups can alternatively be removed at any other appropriate time. It is preferred to deprotect these side chains at the same time as the peptide is cleaved from the resin.
- the compounds are then isolated and purified by standard techniques.
- the desired amino acids, derivatives and isomers thereof can be obtained commercially or can be synthesized according to standard practices and procedures well known in the art.
- APP amyloid precursor protein
- the compounds provided herein yield a positive result in one or more in vitro assays that assess the effects of test compounds on processing of APP.
- in vitro assay systems for identifying such compounds are provided herein. These assays evaluate the effects of a test compound on processing of APP and use cultured human glioblastoma cell lines that have been transfected with DNA encoding either a wild-type 695 amino acid isoform of APP or a mutein of that APP that contains changes (in this case two or three amino acid changes have been made) that appear to make the molecule more susceptible to proteolytic cleavage that results in increased production of A ⁇ see, e., Mullan et al. (1992) Nature Genet. 1:345-347!.
- a test compound is added to the culture medium and, after a selected period of time, the culture medium and/or cell lysates are analyzed using immunochemical assays to detect the relative amounts of A ⁇ , total soluble APP (sAPP), a portion of sAPP designated ⁇ -sAPP, and C-terminal fragments of APP.
- sAPP total soluble APP
- ⁇ -sAPP a portion of sAPP designated ⁇ -sAPP
- C-terminal fragments of APP C-terminal fragments of APP.
- the culture medium and cell lysates are analyzed by immunoblotting coupled with laser scanning densitometry and ELISAs using several different antibodies.
- a positive test occurs when: (1) there is a decrease in the ⁇ 4-kDa amyloid, ⁇ -protein (A ⁇ ) in the medium relative to control cultures (4-kDa assay); and/or (2) the relative amount of total sAPP in the medium increases; and/or (3) there is a decrease in the amount of C-terminal amyloidogenic fragments larger than 9 kDa and smaller than 22 kDa in the cell lysate as a result of differential processing; and/or (4) there is an increase in the amount of ⁇ -sAPP in the medium relative to control cultures.
- Control cultures can be cultures that have not been contacted with the compound.
- the A ⁇ assay is done using cells (eM, HGB 717/Swed) that have been transfected with DNA encoding the mutein APP; the other assays are performed using cells, such as HGB695 cells, that have been transfected with DNA encoding a wild-type APP.
- Preferred compounds have activity that is at least 2-fold, preferably 5-fold, most preferably 10-fold greater activity than N-Acetylleucylleucyl-norleucinal see, e.g., EP 0 504 938 A2; and Sherwood et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:3353-3357! in at least one, preferably the A ⁇ assay, of these assays.
- CSF cerebrospinal fluid
- ⁇ -sAPP and the ratio of ⁇ -sAPP to total sAPP in CSF are shown herein to be useful markers in the detection of neurodegenerative disorders characterized by cerebral deposition of amyloid (e.g., AD) and in monitoring the progression of such disease. Furthermore, assay systems incorporating these markers can be used in monitoring therapeutic intervention of these diseases.
- the amount of ⁇ -sAPP and the ratio of ⁇ -sAPP to total sAPP in CSF samples can be used as an indicator of Alzheimer's Disease and other neurodegenerative disorders.
- this amount and/or the ratio can also be used to assess the effectiveness of compounds provided herein in treating Alzheimer's Disease and neurodegenerative disorders.
- Alzheimer's disease (as diagnosed by other indicia, or confirmed by autopsy) have a statistically significant lower ratio of ⁇ -sAPP to total sAPP in CSF and also have statisticaly significant lower levels of ⁇ -sAPP. Therefore, by comparison with non-Alzheimer's disease controls or by existence of a ratio lower than a predetermined standard, based, for example, on averages in samples from large numbers of unafflicted individuals, or an amount of ⁇ -sAPP lower than a predetermined standard, Alzheimer's disease or, depending upon other indications, another neurodegenerative disease is indicated.
- Compounds, such as those provided herein, that alter this ratio or the level of ⁇ -sAPP closer to that of individuals who do not have a neurodegenerative disorder characterized by the cerebral deposition of amyloid are considered useful for treating these disorders.
- the ability of compounds to modulate processing of APP can also be evaluated in vivo see, e., Kowall et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88:7247-7251!.
- Compounds can be administered through a canula implanted in the cranium of a rat or other suitable test animal see, e., Lamb et al. (1993) Nature Genet. 5:22-29; Pearson et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:10578-10582!. After a predetermined period of administration the rats are sacrificed.
- the hippocampi are evaluated in immunoblot assays or other suitable assays to determine the relative level of ⁇ -sAPP and C-terminal fragments of APP compared to untreated control animals. Compounds that result in relative increases in the amount of ⁇ -sAPP are selected.
- compositions that contain therapeutically effective amounts of the compounds of formulae (I) and (II).
- the compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation.
- suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation.
- suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation.
- suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation.
- the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art.
- a compound or mixture of compounds for Formulae I and II or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
- a physiologically acceptable vehicle carrier, excipient, binder, preservative, stabilizer, flavor, etc.
- the amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained.
- compositions one or more compounds of formulae (I) and (II) are mixed with a suitable pharmaceutically acceptable carrier.
- a suitable pharmaceutically acceptable carrier Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like.
- Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art.
- the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
- compositions suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
- active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action or have other action.
- the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
- solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as tween, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts of the compounds or prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
- cosolvents such as dimethylsulfoxide (DMSO)
- surfactants such as tween
- dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
- the concentrations of the compounds are effective for delivery of an amount, upon administration, that ameliorates the symptoms of the disorder for which the compounds are administered.
- the compositions are formulated for single dosage administration.
- the compounds of formulae (I) and (II) may be prepared with carriers that protect them against rapid elimination from the body, such as time release formulations or coatings.
- Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems,
- the active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated.
- the therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder.
- compositions can be enclosed in ampules, disposable syringes or multiple or single dose vials made of glass, plastic or other suitable material. Such enclosed compositions can be provided in kits.
- the concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
- the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
- the compound should be provided in a composition that protects it from the acidic environment of the stomach.
- the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
- the composition may also be formulated in combination with an antacid or other such ingredient.
- Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules.
- the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules or troches.
- Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as, but not limited to, gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose, starch and lactose, a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a glidant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, and fruit flavoring.
- a binder such as, but not limited to, gum tragacanth, acacia, corn starch or gelatin
- an excipient such as microcrystalline cellulose, starch and lactose, a disintegrating agent such as, but not limited to, alginic acid and corn
- the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
- dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
- the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
- a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
- the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action.
- Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc.
- a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc.
- a synthetic fatty vehicle like ethyl oleate or the like, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- Parenteral preparations can be enclosed in ampules, disposable syringes or multiple dose vials made of glass, plastic or other suitable material. Buffers, preservatives, antioxidants and the like can be incorporated as required.
- suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropyleneglycol and mixtures thereof.
- PBS physiological saline or phosphate buffered saline
- suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropyleneglycol and mixtures thereof.
- Liposomal suspensions, including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No. 4,522,811.
- the active compounds may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
- carriers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of such formulations are known to those skilled in the art.
- the compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application.
- Such solutions may be formulated as 0.01-100% (weight to volume) isotonic solutions, pH about 5-7, with appropriate salts.
- the compounds may be formulated as aeorsols for topical application, such as by inhalation see, em, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923!.
- the compounds may be packaged as articles of manufacture containing packaging material, an acceptable composition containing a compound of formulae (I) and (II) provided herein, which is effective for treating the particular disorder, and a label that indicates that the compound or salt thereof is used for treating the disorder.
- the compounds for use in the the methods herein have the formulae (I) and (II): ##STR5## or the hydrates and isosteres, diastereomeric isomers and mixtures thereof, or pharmaceutically acceptable salts thereof in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R A , R B , X, Q and n are selected from among (i), (ii), (iii), (iv), (v), (vi), (vii) or (viii), as described above.
- the dose ranges which can be established empirically, for use in the treatment of disease states will depend upon the etiology, nature, and severity of the disease state as well as such other factors as determined by the attending physician.
- the broad range for effective treatment is about 0.01 to 10 mg per kilogram (kg) of body weight per day.
- the preferred range is about 0.1 to 10 mg/kg of body weight per day.
- the active compounds can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
- Preferred modes of administration include oral and parenteral modes of administration.
- dosages can be empirically determined by the physician. As these techniques involve the use of cerebrospinal fluids, such techniques, and other equivalently functioning procedures, will be useful to the attending physician in determining the need to modify the dosage for individual patients.
- Amyloid plaques are believed to accompany and/or be involved in the process responsible for the development and progression of certain neurodegenerative disease states. Without being bound by any theory of action, it is believed that the compounds provided herein modulate the generation of amyloidogenic peptides to effectuate a beneficial result. Without any intent to limit -or restrict- the compounds and methods provided herein to any specific mechanism of action for the end-use applications, it is believed that the compounds effectuate a modulation of the processing of the amyloid precursor protein (APP), the progenitor of the deposited amyloidogenic A ⁇ peptides (39 to 43 amino acid residues) found in senile plaques in the brains of patients diagnosed with, for example, Alzheimer's disease.
- APP amyloid precursor protein
- a ⁇ peptides 39 to 43 amino acid residues
- the compounds provided herein are useful in the treatment of such neurodegenerative disease states in which such amyloid plaques accumulate or are implicated in the etiology thereof, including, but not limited to: Alzheimer's disease, cognition deficits, Down's Syndrome, Parkinson's disease, cerebral hemorrhage with amyloidosis, dementia pugilistica, head trauma and in the treatment of conditions characterized by a degradation of the neuronal cytoskeleton resulting from a thrombolytic or hemorrhagic stroke.
- the compounds can be used in the treatment of Alzheimer's patients through the modulation of APP processing to effectuate a beneficial result by: (a) decreasing the formation of A ⁇ ; (b) modulating the generation of a mutually exclusive, alternative-processed form of APP that precludes A ⁇ formation ( ⁇ -sAPP); and/or, (c) modulating the generation of partially processed C-terminal A ⁇ -containing amyloidogenic peptides.
- these compounds may also beneficially modulate neurodegenerative abnormalities not thought to be associated with amyloid plaques, such as stroke, by beneficially affecting the rate of degeneration of the neuronal cytoskeleton that occurs as a result of thrombolytic or hemorrhagic stroke.
- the compounds can be administered to patients in need of such treatment in a dosage range of 0.01-10 mg per kg of body weight per day, and can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
- the dose will vary depending on severity of disease, weight of patient and other factors which a person skilled in the art will recognize.
- Patients include those with a neurodegenerative disease, including but not limited to Alzheimer's disease, cognition deficits, Down's Syndrome, Parkinson's disease, cerebral hemorrhage with amyloidosis, dementia pugilistica, and head trauma. Treatment is effected by administering to such patient a therapeutically effective amount of a compound of the formulae (I) and (II) defined as above.
- a neurodegenerative disease including but not limited to Alzheimer's disease, cognition deficits, Down's Syndrome, Parkinson's disease, cerebral hemorrhage with amyloidosis, dementia pugilistica, and head trauma.
- Particularly preferred for use in these methods are the compounds particularly provided herein the of formulae (I) and (II) but with the proviso that, when the compounds have formula (I): (11360 ) at least one the amino acid residues in the resulting tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) when X is an aldehyde, the non-naturally occurring amino acid (or side chain thereof) is other than norleucine or norvaline, and when the compounds have formula (II) and X is an aldehyde, R 1 is not be norleucine or norvaline.
- the compounds of formula (II) are also selected such that: (1) at least one of the amino acid residues in the resulting di-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 and R 3 is not a side chain of a naturally-occurring amino acid; and (2) when X is an aldehyde, the non-naturally occurring amino acid (or side chain thereof) is other than norleucine or norvaline.
- the compounds have formulae I or II, particularly formula I, as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting di or tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) when R 1 is the side chain from a non-naturally occurring amino acid, it is not the side chain of norleucine or norvaline.
- the compounds have formulae I or II, particularly formula I, as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting di or tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) none of R 1 , R 3 and R 5 is the side chain of norleucine or norvaline.
- the compounds for use in this method of treatment have formulae I or II, particularly formula I, as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) when R 1 is the side chain from a non-naturally occurring amino acid, it is not the side chain of norleucine or norvaline.
- the compounds of formula (II) are also selected such that: (1) at least of one the amino acid residues in the resulting dipeptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 and R 3 is not a side chain of a naturally-occurring amino acid; and (2) when X is an aldehyde, the non-naturally occurring amino acid (or side chain thereof) is other than norleucine or norvaline.
- the compounds have formulae I or II, particularly formula I, as defined above, but with the proviso that: (1) at least one of the amino acid residues in the resulting di or tri-peptide is a non-naturally-occurring ⁇ -amino acid or at least one of the R 1 , R 3 and R 5 is not a side chain of a naturally-occurring amino acid; and (2) none of R 1 , R 3 and R 5 is the side chain of norleucine or norvaline.
- the compounds provided herein have activity as inhibitors of proteases, such cysteine proteases, including calpain. It is believed by those of skill in this art that excessive activation of the Ca 2+ -dependent protease calpain plays a role in the pathology of a variety of disorders, including cerebral ischaemia, cataract, myocardial ischaemia, muscular dystrophy and platelet aggregation. Thus, compounds that have activity as calpain inhibitors are considered by those of skill in this art to be useful see, e g, U.S. Pat. No. 5,081,284, Sherwood et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:3353-3357!.
- Assays that measure the anti-calpain activity of selected compounds are known to those of skill in the art (see, e., U.S. Pat. No. 5,081,284). Activities of inhibitors in such in vitro assays at concentrations (IC 50 ) in the nanomolar range or lower are indicative of therapeutic activity. Such compounds also have utility in the purification of proteinases, such as cysteine proteases, on affinity columns of these compounds (see, U.S. Pat. No. 5,081,284). Also, calpain inhibtors, such as N-Acetylleucylleucyinorleucinal see, e., EP 0 504 938 A2; and Sherwood et al. (1993) Proc.
- reaction mixture was stirred for 16 h. Additional CH 2 Cl 2 (25 mL) was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate (sat. NaHCO 3 ) (2 ⁇ 10 mL), 10% aqueous hydrogen chloride (10% HCl) (2 ⁇ 10 mL), saturated aqueous sodium chloride (sat. NaCl) (2 ⁇ 10 mL), dried over anhydrous magnesium sulfate (MgSO 4 ), filtered and concentrated.
- saturated aqueous sodium hydrogen carbonate sat. NaHCO 3
- 10% aqueous hydrogen chloride (10% HCl) (2 ⁇ 10 mL
- saturated aqueous sodium chloride sat. NaCl
- N-Boc-L-(methyl)Nle N-methoxy-N-methylamide (0.84 g, 2.9 mmol) was treated with 4N HCl in dioxane (15 mL) at R.T. The reaction mixture was stirred for 1.5 h then concentrated in vacuo. The solid was treated with anhydrous ether (3 ⁇ 10 mL) and concentrated in vacuo.
- N-L-(methyl)Nle N-methoxy-N-methylamide hydrochloride was isolated as a white solid (0.47 g, 85.7%): 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.91-0.95 (m, 3 H), 1.73 (m, 4 H), 2.06-2.08 (m, 2 H), 2.27-2.29 (m, 6 H), 3.71-4.09 (m, 3 H) ppm.
- N-Boc-L-Nle N-methoxy-N-methylamide (1.0 eq) in anhydrous THF (10 mL) at 0° C. under Ar is added LiAlH 4 (1.0 eq), and stirred for 3 h at 0° C. followed by the addition of 1N HCl (1 mL).
- the mixture is taken up in EA then washed with sat. NaHCO 3 , 1N HCl, sat. NaCl, dried (MgSO 4 ), filtered and concentrated to afford the N-Boc-L-norleucinal as a crude residue.
- Example 15 To the product obtained from Example 15 in anhydrous ether at 0° C. is added diazomethane. After 3 h the solvent is removed and the residue is purified by flash chromatography on silica gel to give the desired product.
- Example 15 To the product of Example 15 in anhydrous CH 2 Cl 2 under Ar at R.T. is added HOBT (1.0 eq), EDC (1.0 eq), Et 3 N (1.0 eq) and benzylamine (1.0 eq). After 6 h the reaction mixture is washed with sat. NaHCO 3 , sat. 1N HCl, sat. NaCl, dried (MgSO 4 ), filtered and concentrated. The residue is purified by flash chromatography on silica gel to afford the desired product.
- N-Boc-L-norleucinal prepared by reducing N-Boc-L-Nle N-methoxy-N-methylamide as described in Example 15, in THF at -78° C. under Ar is added ethyl lithioacetate (2.2 eq) prepared in situ by the addition of nBuLi (2.2 eq) to excess anhydrous ethyl acetate.
- ethyl lithioacetate 2.2 eq
- nBuLi 2.2 eq
- the reaction mixture is treated with 1N HCl, and the organic layer is washed with 1N HCl, sat. NaHCO 3 . sat. NaCl, dried (Mg SO 4 ), filtered and concentrated. Purification by flash chromatography on silica gel gives the ester.
- the ester is treated with 4NHCl/dioxane for 30 min, then concentrated in vacuo.
- the resulting solid is taken up in anhydrous ether and concentrated in vacuo to give the hydrochloride.
- the hydrochloride is used without further purification in the next step.
- Example 3 Using the procedure set forth in Example 3 the title compound was isolated as a yellowish solid (50.0 mg): Reporting a mixture of diastereomers 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.87-1.72 (ol-m, 29 H), 1.99+2.00 (s+s, 3 H), 4.35-4.75 (ol-m, 3 H), 6.57-7.82 (ol-m, 3 H), 9.56-9.63 (ol-m, 1 H) ppm.
- N-Ac-L-Leu-L-Leu-DL-norleucinal was isolated as a white solid (0.1 2 g) using similar methodology that is set forth in Example 3: Reporting a mixture of diatereomers 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.81-0.88 (ol-m, 9 H), 1.23-1.83 (ol-m, 8 H), 1.94-1.96 (s+s, 3 H), 2.96-3.21 (ol-m, 0.4 H), 3.31-3.47 (ol-m, 2 H), 4.02-5.10 (ol-m, 3 H), 7.05-7.20 (ol-m, 5 H) 9.20-9.49 (ol-m, 0.6 H) ppm.
- Example 2 Using the procedure set forth in Example 2 the title compound was isolated as a colorless oil (0.22 g): 1 H NMR (CDCl 3 , 200 MHz) ⁇ 0.86-0.93 (m, 9 H), 1.23-1.86 (m, 9 H), 2.37 (m, 0.2 H), 3.90 (s, 2 H), 4.39-4.51 (m, 1 H), 4.57-4.61 (m, 1 H), 5.08 (m, 2 H), 5.94 (hs, 1 H), 7.12-7.23 (m, 2 H), 7.23-7.32 (m, 5 H), 9.49 (s, 0.8 H) ppm.
- Human glioblastoma cells (ATCC Accession No. HTB16) were stably transfected with a DNA expression vector encoding a 695 amino acid isoform variant of the amyloid precursor protein (APP) containing the familial Swedish double mutations at codons 670 and 671 (K to N and M to L, respectively; see Mullan et al. (1992) Nature Genet. 1:345-347) and an additional mutation at codon 717 (V to F; see Murrell et al. (1991) Science254:97-99) to produce cells designated HGB 717/Swed. High levels of A ⁇ are detectable in the conditioned medium isolated from HGb 717/Swed cultured cells. The medium also contains larger secreted fragments, ⁇ -sAPP 695 , which are alternatively processed APP fragments whose generation precludes A ⁇ formation.
- APP amyloid precursor protein
- HGB 717/Swed cells were grown at 37° C. under a 5% carbon dioxide atmosphere in Dulbecco's modified eagle medium (DMEM; Gibco) supplemented with 10% heat-inactivated fetal calf serum, 0.45% glucose, 2 mM L-glutamine, 100 units/ml penicillin, and 100 ⁇ g/ml streptomycin sulfate (Gemini Bioproducts). Approximately 1 ⁇ 10 6 cells were incubated overnight in 5 ml of DMEM containing varying ⁇ M final concentrations of desired test compounds or a DMSO control. Conditioned medium was collected, and unwanted cells and debris were removed by sedimentation at 3,000 rpm at 4° C.
- DMEM Dulbecco's modified eagle medium
- a ⁇ peptides were isolated from the medium by immunoaffinity purification using an A ⁇ -specific antibody.
- the medium was pre-treated with rabbit antisera and Protein A Sepharose (Pharmacia) for 4 hours at 4° C.
- the sepharose-bound material was removed by centrifugation at 3,000 rpm at 4° C. for 10 min, and A ⁇ peptides were immunoaffinity purified from the clarified medium by incubation overnight with an affinity purified polyclonal rabbit antibody (referred to as 2939) prepared against a synthetic A ⁇ peptide corresponding to amino acids 1 to 28.
- an affinity purified polyclonal rabbit antibody referred to as 2939
- Protein A-conjugated sepharose was added to immobilize the A ⁇ -antibody complexes, and the resin was pelleted by centrifugation at 3,000 rpm at 4° C. for 10 min.
- the A ⁇ -antibody complexes were eluted from the matrix by denaturing the complex by boiling in the presence of SDS.
- Human glioblastoma cells (ATCC Acession No. HTB16) were stably transfected with a DNA expression vector encoding the 695 amino acid isoform of the amyloid precursor protein (APP 695 ).
- the resulting cells are designated HGB695 cells.
- High levels of secreted proteolytic processed fragments of APP 695 (sAPP 695 ) are detectable in the culture medium (sAPP 695 ).
- DMEM Dulbecco modified eagle medium
- penicillin 100 ⁇ g/ml streptomycin sulfate and 2 mM L-glutamine.
- the medium was removed and 1 ml of supplemented DMEM medium containing 5 ⁇ l of DMSO or DMSO containing the desired test compound within a range about 5 to 100 ⁇ M (final concentration in the well), was added to each well, and incubation was continued for 24 hours. Unwanted cells and debris were removed by sedimentation at 3,000 ⁇ g for 10 min at room temperature. Supernatants were stored at -20° C. for analysis.
- a capture antibody such as monoclonal antibody P2-1 , which recognizes an epitope located in the amino terminus of APP (see, em, U.S. Pat. No. 5, 20 270,165) was attached to the wells of a 96 -well microtiter by incubating the antibody in the plate for 60 min at 37° C.
- the plates were washed three times with 0.3 ml of 0.1% Tween-20 in phosphate-buffered saline (PBS).
- PBS phosphate-buffered saline
- the non-specific interaction of unrelated proteins (such as serum proteins that may interfere with the analysis) with the antibody was reduced by incubating the pretreated wells for 30 min at 37 ° C. with a solution of 0.5% casein in PBS (150 ⁇ l/well).
- Wells were washed thoroughly with 0.1 % Tween-20 in PBS prior to analysis of samples.
- the conditioned medium supernatant was diluted 1:20 in 0.95 ml of 0.1% CHAPS (3- (3-cholamidopropyl)-dimethylammonio!-1-propane-sulfonate) in PBS.
- CHAPS 3- (3-cholamidopropyl)-dimethylammonio!-1-propane-sulfonate
- Supernatant samples 100 ⁇ l/well or sAPP standards (100 ⁇ l/well) of a range about 5 to 50 ng/ml were added to the pre-treated wells and incubated for 60 min at 37° C. The supernatant was removed and each sample well was washed as described above.
- HRP horseradish peroxidase conjugated goat affinity purified antibody, raised against sAPP 695 , was diluted in 0.1 % Tween-20 in PBS and 10% goat serum and employed as the "signal antibody".
- the unbound antibody was removed by washing, and to each well, 0.1 ml of the chromagenic substrate K-Blue Solution (Elisa Technologies, Lexington, Ky.) was added and samples were incubated for 15 min at ambient temperature. Reactions were stopped by the addition of 0.1 ml of a 9.8% solution of phosphoric acid.
- the optical density of samples was measured by spectrophotometry at 450 nm.
- the concentration of sAPP 695 peptides in the conditioned medium was estimated from the sAPP 695 standard curve. Samples were analyzed in duplicate with the appropriate standards and reference controls (i.e., a known protease inhibitor compound, such as N-acetylleucylleucyinorleucinal of given potency and concentration!
- HGB695 human glioblastoma cells were employed and grown in 12-well dishes essentially as described in Example 31B with the following modifications.
- the DMEM growth media were supplemented with varying ⁇ M concentrations of compounds or DMSO control and 100 ⁇ M leupeptin and 1 ⁇ M PMA phorbol ester and were incubated with cell cultures for 16 hours and cells were grown to approximately 2.5 ⁇ 10 6 cells per well.
- the nitrocellulose membrane was washed three times in PBS and then incubated in PBS containing a 1:5000 dilution of a rabbit polyclonal antibody raised against the C-terminal 19 amino acids of APP (provided by S. Gandy, Rockefeller University, NY).
- the nitrocellulose membrane was washed as described above and incubated with a secondary biotinylated goat anti-rabbit lgG antibody. Specifically bound antibody was detected using a streptavidin horseradish peroxidase conjugate, and visualized in combination with an enhanced chemoluminescent detection kit (Amersham).
- Potentially amyloidogenic peptides greater than 9 and less than 22 kDa were quantitated by densitometric scans of developed films within the linear range as described in Example 31B.
- a positive result for a compound in the cell lysate assay is denoted by a decrease in the levels of the protein bands greater than 9 and less than 22 kDa relative to the appropriate control samples.
- Human HGB695 glioblastoma cells transfected with DNA encoding the 695 amino acid isoform of APP were grown and treated with test compound or DMSO as described in Example 31B.
- Medium from the cultured cells was obtained as described in Example 31B and analyzed for ⁇ -sAPP in an ELISA assay as follows.
- the wells of a 96-well microtiter plate were coated with a monoclonal antibody that specifically recognizes the amino terminus of human sAPP (e.g., monoclonal antibody P2-1) by incubating the antibody in the plate for 60 min at 37° C.
- the plates were washed three times with 0.3 ml of 0.1 % Tween-20 in PBS.
- the conditioned media were diluted 1:20 in 0.95 ml of 0. 1 % CHAPS in PBS.
- Media samples 100 ⁇ l/well
- ⁇ -sAPP standards 100 ⁇ l/well
- a horseradish peroxidase-conjugated rabbit affinity purified antibody raised against a synthetic peptide consisting of the first 1 5 amino acids of A ⁇ (referred to as antibody 3369) was diluted in 0.1 % Tween-20 in PBS plus 10% normal rabbit serum and added to the wells as the signal antibody.
- the plates were incubated for 60 min at 37° C. and then washed to remove unbound antibody.
- the chromogenic substrate K-Blue Solution (Elisa Technologies, Lexington Ky.) was added to the wells (0.1.) ml well and allowed to incubate for 15 min at ambient temperature. The reactions were stopped by addition of 0.1 ml of a 9.8% solution of phosphoric acid. The optical density of the samples was measured by spectrophotometry at 450 nm. The concentration of ⁇ -sAPP in the media was estimated from the ⁇ -sAPP standard curve. Samples were analyzed in duplicate.
- APP 670/671 mutation in the Swedish family is associated with a high incidence of early onset Alzheimer's disease (AD).
- the clinical diagnosis of AD in the Swedish family harboring the mutation was based on NINCDS-ADRDA criteria McKhann, et al. (1984) Neurology34:939-944!. The diagnosis was confirmed by neuropathologic examination of the brain of one deceased mutation carrier Lannfelt, et al. (1994) Neurosci. Lett. 168:254-256!.
- MMSE Mini Mental State Examination
- PCR polymerase chain reaction
- Lumbar CSF was obtained from eight normal non-carriers in the family, two presymptomatic healthy mutation carriers, and four mutation carriers clinically symptomatic for AD. CSF samples were placed on ice, aliquoted and stored at -20° C. until tested.
- Total sAPP and ⁇ -sAPP levels in the CSF samples were quantitated using a sandwich enzyme-linked immunosorbent assay (ELISA) and immunoblotting followed by laser-scanning densitometry, respectively.
- ELISA sandwich enzyme-linked immunosorbent assay
- Standards used in the assays were obtained by isolation of total sAPP and ⁇ -sAPP from medium conditioned by human neuroblastoma IMR32 cells ATCC Accession No. CCL127! or the HGB695 cells, described above in Example 31B, as follows. Conditioned medium was filtered to remove large cell debris, and sAPP was extracted by passing the media over an anion exchange column using Toyopearl DEAE 650C resin (Toso-Hass, Philadelphia, PA). The bound sAPP was eluted from the column using a linear gradient of 0 to 0.6 M NaCl in 50 mM sodium phosphate, pH 7.5.
- sAPP-containing eluate fractions were pooled and loaded onto an immunoaffinity column containing a monoclonal antibody that specifically recognizes an amino-terminal epitope of human APP (for example, monoclonal antibody P2-1 raised against native human PN-2) see, ec, U.S. Pat. No. 5,213,962! linked to Toyopearl AF-Tresyl 650 M resin (TosoHass). Bound sAPP was eluted from the column with 0.1 M sodium citrate, pH 2.0.
- the total sAPP was loaded onto a Sepharose 4B immunoaffinity adsorption column containing a monoclonal antibody that recognizes an epitope within the first ⁇ 17 amino acids of A ⁇ (for example, monoclonal antibody 6E10).
- a monoclonal antibody that recognizes an epitope within the first ⁇ 17 amino acids of A ⁇ (for example, monoclonal antibody 6E10).
- ⁇ -sAPP was eluted from the column with 0.1 M sodium citrate, pH 3.0.
- the solution pH of the purified sAPPs was adjusted to 7.2 and 1-ml aliquots were stored at -70° C.
- the ELISA used to quantitate total sAPP levels in CSF samples employed a monoclonal antibody, such as P2-1, discussed above, that specifically recognizes an amino-terminal epitope of human APP as the capture antibody.
- the capture antibody was attached to the wells of a 96-well microtiter plate by incubating the plate with the antibody (that had been diluted in PBS, pH 7.2) for 60 min at 37° C. The plates were then washed three times with 0.3 ml of 0.1 % Tween-20 in PBS. The wells were also incubated with a solution of 0.5% casein in PBS (150 ⁇ l/well) for 30 min. at 37 ° C.
- CSF samples 100 ⁇ l diluted 1:20
- sAPP standards 100 ⁇ l containing a range of 5 to 50 ng/ml were added to the wells and allowed to incubate for 60 min at 37° C. Following incubation, the wells were washed thoroughly with 0.1 % Tween-20 in PBS.
- a goat anti-human APP polyclonal antibody raised against immunopurified APP from medium conditioned by cultured IMR32 human neuroblastoma cells (American Type Culture Collection Accession No. 127) conjugated to horseradish peroxidase was used as the signal antibody.
- the antibody was diluted 1:500 in PBS and 10% normal goat serum, pH 7.2, containing 0.
- Total sAPP levels were also measured using quantitative immunoblotting essentially as described below for measurement of ⁇ -sAPP, except using a monoclonal antibody raised against a recombinant APP-containing fusion protein (e.g., 22C11 available from Boehringer Mannheim, Indianapolis, IN) at a concentration of 0.3 ⁇ g/ml to specifically detect sAPP and using purified sAPP as a standard. Quantification of total sAPP by quantitative immunoblot gave a 95% correlation to quantification by ELISA.
- a monoclonal antibody raised against a recombinant APP-containing fusion protein e.g., 22C11 available from Boehringer Mannheim, Indianapolis, IN
- Nonspecific binding of protein to membranes was blocked with PBS containing 5% (w/v) non-fat dried milk and then incubated for 1 hr with a monoclonal antibody (20 ml of 0.2 ⁇ g/ml) directed against the amino-terminus of A ⁇ (e.g., 6E10), and washed three times for one min each time in 20 ml of PBS and 0.1% Tween.
- a monoclonal antibody (20 ml of 0.2 ⁇ g/ml) directed against the amino-terminus of A ⁇ (e.g., 6E10), and washed three times for one min each time in 20 ml of PBS and 0.1% Tween.
- Specifically bound antibody was detected using a biotinylated goat anti-mouse secondary antibody (Sigma) and a streptavidin-peroxidase conjugate (Amersham, Arlington Heights, Ill.) in combination with an enhanced chemiluminescence detection system (Amersham, Arlington Heights, Ill.
- the blots were exposed to Kodak Scientific Imaging film X-OMAT AR and developed using a Kodak X-OMAT developer. Quantitation of the ⁇ -sAPP protein in the blots was performed by laser-scanning densitometry. Developed films within the linear range (or multiple exposures) were scanned at 50 ⁇ M pixel size using a densitometer (Molecular Dynamics, Sunnyvale, CA), and the data were quantified using the ImageQuaNT software system (Molecular Dynamics). Quantified volumes of ⁇ -sAPP standard were used to generate standard curves. From the standard curves, the levels of ⁇ -sAPP in ng/ml were determined.
- ⁇ -sAPP and the ratio of ⁇ -sAPP to total sAPP in CSF are useful markers in the detection of neurodegenerative disorders characterized by cerebral deposition of amyloid (e.g., AD) and in monitoring the progression of such disease. Furthermore, this assay system can be used in monitoring therapeutic intervention of these diseases.
Abstract
Description
______________________________________ INHIBITION OF Aβ FORMATION COMPOUND % INHIBITION OF Aβ ______________________________________ Ac--L--L--Nl--(DM) 87.sup.a Cbz--L--L-- CH3!--Nl--(H) 97.sup.b Ac--L--L--Nl--(CN) 94.sup.a Cbz--L--F--Lene--(H) 69.sup.c Ac--L--L--Chg--(H) 99.sup.a Cbz--L--F--Cha--(H) 100.sup.b Ac--L--L--Cha--(H) 46.sup.c Ac--L--L--Nlene--(H) 96.sup.a Cbz--P--L--Nl--(H) 80.sup.b Cbz--L--L--Lene--(H) 95.sup.c Cbz--L-- CH3!--L--Nl--(H) 77.sup.b 2S-benzoxyvaleric-L--Lene--(H)* 85.sup.b Ac--L--L--Nl--(TFMK) 50.sup.a Fmoc-L--L--Nl--(H) 89.sup.d ______________________________________ .sup.a Inhibition of Aβ formation was determined at a concentration of 75 μM. .sup.b Inhibition of Aβ formation was determined at a concentration of 40 μM. .sup.c Inhibition of Aβ formation was determined at a concentration of 10 μM. .sup.d Inhibition of Aβ formation was determined at a concentration of 50 μM. *dipeptide Nl norleucine Lene 2amino-4-methyl-4-pentenoic acid (unsaturated isobutyl leu side chain) Nlene 2amino-4-hexenoic acid (unsaturated nbutyl Nle side chain) (H) aldehyde (TFMK) trifluoromethylketone (DM) diazomethylketone (CN) nitrile
Claims (21)
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US08/403,420 US5969100A (en) | 1995-01-06 | 1995-03-13 | Peptide, peptide analog and amino acid analog protease inhibitors |
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US5969100A (en) | 1999-10-19 |
CA2209234A1 (en) | 1996-07-11 |
AU4697296A (en) | 1996-07-24 |
US6153171A (en) | 2000-11-28 |
ATE227305T1 (en) | 2002-11-15 |
US5962419A (en) | 1999-10-05 |
US5714471A (en) | 1998-02-03 |
US6015879A (en) | 2000-01-18 |
DK0800528T3 (en) | 2002-11-25 |
JPH11514330A (en) | 1999-12-07 |
EP0800528B1 (en) | 2002-11-06 |
EP0800528A1 (en) | 1997-10-15 |
US6051684A (en) | 2000-04-18 |
WO1996020949A1 (en) | 1996-07-11 |
DE69624681D1 (en) | 2002-12-12 |
DE69624681T2 (en) | 2003-07-03 |
PT800528E (en) | 2003-02-28 |
ES2184850T3 (en) | 2003-04-16 |
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